Diphenhydramine, i.e., 2-diphenylmethoxy-N,N-dimethylethanamine, is a well-known antihistamine. Since the compound is insoluble in water, it typically is administered in the form of its hydrochloride salt. Diphenhydramine hydrochloride has the molecular formula C17H21NO.HCl, a molecular weight of 291.82, a melting point of 166–170° C. and a bitter taste. The hydrochloride is quite soluble in water (1 gram dissolves in 1 ml of water). It is typically administered to human beings in need of such medication in the form of tablets and/or suspensions. It frequently is administered as an antihistamine/antitussive composition consisting of diphenhydramine hydrochloride/dextromethorphan hydrobromide monohydrate.
The currently administered forms of diphenhydramine, i.e., generally an acid salt such as the hydrochloride, are disadvantageous in that they are absorbed very quickly in the mammalian body. Accordingly, although such forms provide prompt relief, multiple doses must be taken on a daily basis to provide an effective level of medicament over the prescribed period of treatment (generally several days to one week).
It would be very desirable if a form of diphenhydramine was available which would have extended-release properties, i.e., the diphenhydramine would be slowly released into the patient's bloodstream over a prolonged period of time. Until recently, the only slow-release forms of diphenhydramine that were available were those such as polymer-coated tablets. Such prior art formulations provided mixed results in that the diphenhydramine was not available for adsorption into the patient's bloodstream until the polymeric coating was dissolved, but thereafter the diphenhydramine was quickly absorbed and metabolized. The result is that frequently, the diphenhydramine had to again be administered to the patient within the period of only a few hours.
The foregoing problem was solved by converting the diphenhydramine free base into its tannate salt by reaction of the free base with tannic acid. The tannate salt stabilizes the diphenhydramine free base and, most importantly, imparts extended release properties to the diphenhydramine. In recent years, tannate salts of antihistamines have become known, e.g., see U.S. Pat. Nos. 5,599,846; 5,663,415; 6,037,358; 6,287,597; and 6,306,904.
Tannic acid is commercially available and is used in many industrial applications. It is frequently referred to as gallotannic acid, gallotannin; glycerite or tannin. It is a pale tan powder having a decomposition point of 210–215° C., and is highly soluble in water and alcohols. Its molecular formula is C76H52O46; its CAS number is 1401-55-4. Tannic acid is typically produced from Turkish or Chinese nutgall and has a complex non-uniform chemistry and typically contains about 5–10 wt. % water.
Commercially available antihistamine tannate compositions are relatively impure. Such compositions are typically prepared by reacting the antihistamine free base with tannic acid in the presence of a volatile solvent, usually isopropanol. The yield is only fair (e.g. about 70%) and decomposition products e.g. 2–5 wt. %, and a significant amount of the volatile solvent, e.g. 6–10 wt. %, based on the weight of the composition, remains with the product and cannot be removed.
Typically, in the conventional isopropanol route, the antihistamine free base and the tannic acid will be present in the isopropanol at a concentration of about 20 wt. %, based on the weight of the reaction mixture. The reaction mixture is stirred for about one hour, while maintaining a temperature of 60–70° C. The reaction mixture is cooled to room temperature and filtered. The precipitate is vacuum dried for an extended period of time at a temperature of 60–80° C. A yield of product of only about 70% is obtained and the product purity will be about 85–90 wt. %, based on the weight of the composition (the impurities consist of isopropanol and decomposition products which cannot be removed).
Many antihistamine tannates are heat sensitive and therefore undergo decomposition quite readily upon prolonged exposures to temperatures as low as 50° C. Accordingly, even when the solvent utilized in its preparation has a relatively high vapor pressure such as is in the case of isopropanol, it is impossible to reduce the solvent content below about 6 wt. %, based on the weight of the antihistamine tannate composition, even at reduced pressures and very mild elevated temperatures. Moreover, from an environmental point, it would be most desirable if the antihistamine tannate could be prepared such that the use of volatile solvents could be avoided.
The process disclosed in U.S. Pat. No. 5,663,415 represents a significant improvement over the isopropanol route. The process disclosed in the '415 patent involves three steps:                (a) the antihistamine in the form of its free base is contacted with tannic acid in the presence of water at a maximum temperature which will not cause decomposition of the antihistamine tannate to an extent of greater than about 5 wt %, based on the weight of the antihistamine tannate;        (b) the antihistamine is allowed to remain in contact with the tannic acid in the presence of water for a period of time of about 5 minutes to 4 hours at said maximum temperature; and        (c) the antihistamine tannate resulting from step (b) is freeze-dried at a temperature and at a reduced pressure and for such period of time that (i) at least about 90 wt. % of the water is removed from the antihistamine tannate and (ii) decomposition of the antihistamine tannate will be limited to a maximum of about 5 wt. %.        
The '415 patent discloses a three-step method that results in the production of pure antihistamine tannate compositions having a minimum purity level of at least 90 wt. %, usually at least 95 wt. % and often at least 98 wt. %, based on the weight of the composition, with a yield of at least about 90% and often with a yield in excess of 97%. The chief “impurity” present in the compositions prepared by the process of the '415 patent is water which is present in an amount of 1–5 wt. %, based on the weight of the composition.
Although the process disclosed in the '415 patent represents a dramatic improvement leading to very pure antihistamine tannate compositions, it has several drawbacks: freeze-drying is quite time-consuming (typically 30–36 hours to remove 1 liter of water) and expensive and requires specialized equipment in order to achieve the reduced pressures and temperature required to dry the antihistamine tannate composition, i.e., a pressure of not greater than about 500 milliTorr and a temperature in the range of about −60° C. to −20° C. Such specialized equipment also limits the amount of product that can be processed within a reasonable amount of time.